ReviewPhysiology of FGF23 and overview of genetic diseases associated with renal phosphate wasting
Introduction
Phosphate is a key element for several physiological pathways such as skeletal development, bone mineralization, membrane composition, nucleotide structure, maintenance of plasma pH, and cellular signaling [1]. Phosphate is mainly stored in bone, but the kidneys have a key role in phosphate homeostasis with two hormones playing important roles in renal phosphate handling: parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23). Both hormones have hypophosphatemic effects by decreasing tubular phosphate reabsorption, with opposite effects on the regulation of 1,25-dihydroxyvitamin D (1,25(OH)2D). A third main regulator of phosphate metabolism is 1,25(OH)2D which increases phosphate intestinal absorption and inhibits PTH synthesis. An overview of phosphate physiology, with intestinal absorption, renal excretion, and bone metabolism is provided in Fig. 1 [2].
In adults, hypophosphatemia is defined as phosphatemia below 2.5 mg/dL (0.8 mmol/L), while a level below 1 mg/dL (0.3 mmol/L) is considered severe hypophosphatemia [2]. In children, hypophosphatemia is defined based on the age-related normal range [3]. Children with hypophosphatemia from defects of tubular reabsorption of phosphate (e.g., X-linked hypophosphatemia, or proximal tubulopathy such as the De Toni Debre Fanconi syndrome or Dent disease) experience growth retardation, bone deformities and rickets [4]. In the early 2000s, overexpression of FGF23 was initially described in pediatric patients with autosomal dominant X-linked hypophosphatemia XLH [5], and it was also rapidly associated with tumor-induced osteomalacia (TIO) in adults [6], highlighting the key role of FGF23 and its regulators in phosphate physiology.
The aim of this review is to provide an up-to-date overview of FGF23 physiology and pathophysiology in XLH, with a focus on FGF23-associated genetic diseases.
Section snippets
FGF23 Physiology
FGF23 is a 251 amino-acid protein (molecular weight = 30 kDa) with a 24 amino-acid signal peptide in the N-terminal portion; its chromosome location is 12p13 in humans. It belongs to the FGF family, in the sub-group of the ‘endocrine FGFs’ with FGF19 and FGF21 [7]. Although it shares a highly conserved sequence with all the FGFs, it has a unique C-terminal structure as well as a specific three-dimensional configuration (i.e., disulfide bond and β sheet), both accounting for its systemic action [
FGF23-Associated Diseases in Humans
In humans, both FGF23 and Klotho expression can be modified in genetic or acquired diseases. Four groups can be distinguished: diseases with a primary excess in intact FGF23 levels (e.g., genetic X-linked hypophosphatemia and non-genetic tumor-induced osteomalacia); diseases with a primary deficiency in intact FGF23 levels or inefficient FGF23 (e.g., hyperphosphatemic tumoral calcinosis); diseases with a secondary excess in FGF23 concentration (e.g., chronic kidney disease, CKD), and diseases
Animal Models of FGF23 Deficiency and Excess
FGF23 knock-out mice have decreased longevity, growth retardation, skin atrophy, decreased bone density and ectopic as well as vascular calcifications [50]. In addition, they exhibit hyperphosphatemia, hypercalcemia and elevated serum 1,25(OH)2D [50]. These mice also tend to be more sensitive to insulin and are therefore at increased risk of hypoglycemia. In these animals, correcting serum phosphate levels with low phosphate diet without modifying serum calcium or 1,25(OH)2D levels, improves
Experimental Studies in Animals and in Humans
XLH is a dominant disorder caused by mutations in PHEX located on X-chromosome Xp22.1 [53]. PHEX encodes a cell-surface-bound protein cleavage enzyme and is predominantly expressed in osteoblasts, osteocytes, odontoblasts, muscles, teeth, lungs and ovaries [54]. The pathogenesis of XLH is yet not fully understood. The majority of XLH patients as well as Hyp mice, an orthologous animal model of XLH, have elevated FGF23 levels [55]. Excess FGF23 results in renal phosphate wasting and consequent
Conclusion
The management of patients with XLH remained purely symptomatic until recently, using mainly phosphate supplementation, active vitamin D analogs and native vitamin D [4]. After the demonstration of its efficacy in adults and in children [64], burosumab (a FGF23 antibody) was approved by the European Medicines Agency for children with XLH in 2018. This opens a completely new therapeutic paradigm for these patients, and the development of such a targeted therapy is the direct consequence of the
Contributors
JB wrote the first draft of the manuscript; CB and DP reviewed it. All the authors approved the last version of the manuscript.
Acknowledgements
This article is published as part of a supplement supported by Kyowa Kirin Pharma.
Declaration of Competing Interest
The authors declare no conflict of interest.
Funding information
Not relevant for this review.
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Authors contributions: JB wrote the first draft of the manuscript; CB and DP reviewed it. All the authors approved the last version of the manuscript.